Cough is a biophylactic reaction induced by inhalation of foreign substances, accumulation of sputum in the respiratory tract, and the like. Cough also occurs upon various clinical conditions such as common cold and respiratory tract inflammation. Exhaustion accompanied by cough is intensive, especially in the case of the aged suffering from influenza, and may be a direct cause of death. Further, continuing cough may cause chest pain, urinary incontinence, shortage of sleep, exhaustion, and the like to thereby trouble daily life, and therefore results in QOL deterioration. Cough may be categorized as cough by chronic bronchitis, cough after acute upper respiratory inflammation, cough accompanied by oral administration of an angiotensin-converting enzyme inhibitor, cough by gastroesophageal reflux, cough by sinobronchial syndrome, cough by cough variant asthma, atopic cough, and the like. Cough not only has clinical diversity but also has not yet fully elucidated for its mechanism, and therefore an effective antitussive is considered to be in short supply.
The afferent nerve involved in sensation at the respiratory tract and an onset of cough may be classified broadly into medullated Aδ-fiber and nonmedullated C-fiber. Among them, Aδ-fiber plays an afferent role of a cough reflex and is mostly well distributed in the laryngeal trachea. At a terminal receptor of the Aδ nerve exist RARs (rapidly adapting receptor) that may sensitively react to a mechanical stimulation such as mucus and eventually cause a cough reflex via the cough center but may hardly be affected by an inflammation-related mediator such as bradykinin. On the other hand, C-fiber, occurring at a peripheral part of the lower respiratory tract, is highly sensitive to chemical substances but is not responsive to a mechanical stimulation (Non-patent Reference 1).
A medicament currently used as an antitussive may be broadly classified into a central antitussive and a peripheral antitussive. A central antitussive may suppress a cough reflex by blocking the cough center to thereby exert an antitussive efficacy. A central antitussive may further be classified into narcotic and normarcotic ones. A typical narcotic antitussive includes codeine and dihydrocodeine phosphate. A narcotic antitussive may exert a potent antitussive efficacy but has a problem that it has adverse side effects such as addiction, drowsiness, constipation, nausea, vomiting, headache, hallucination, and the like and may not be used for bronchial asthma accompanied by respiratory tract inflammation or obstructive pulmonary diseases due to induction of bronchial muscle contraction (Patent Reference 1 and Patent Reference 2). A typical normarcotic antitussive includes noscapine, alloclamide hydrochloride, and dextromethorphan hydrobromide. A normarcotic antitussive is said to be free from tolerance or dependence with weak adverse side effects but still affects on those other than the cough center, causing adverse side effects such as dizziness, drowsiness, headache, and the like. Further, its antitussive activity is weaker than that of a narcotic antitussive with almost no efficacy for psychogenic cough or pertussis.
On the other hand, a peripheral antitussive may be classified into a cough drop, a variety of Chinese herbal medicines, a mouthwash, an expectorant, and a bronchodilator. They affect on the laryngeal trachea or the tracheal bifurcation to suppress a cough reflex but, unlike a central antitussive, cannot fully suppress an onset of cough and their effects are relatively slight. Another peripheral antitussive includes a steroid (inhalation and oral agent) and an antihistamine with which some cough, with no amelioration of symptoms, may become chronic, for which any medicament may hardly be effective. Recently, it is suggested that C-fiber may be involved in intractable chronic cough. Therefore, at a clinical stage, an antitussive suppressing cough caused by stimulation at the laryngeal trachea and at the tracheal bifurcation is desired but currently available antitussives are not efficacious (Patent Reference 3).
FXI is a plasma protein which functions at a contact layer of blood coagulation cascade and exists as a homodimer of a molecular weight of approximately 160,000 which comprises single-strand glycoproteins of a molecular weight of approximately 80,000 bound with each other via a single S—S bond. Immature FXI immediately after production is added with a signal sequence, which is cleaved to produce mature FXI. The monomer consists of an N terminal H chain comprising four apple domains, each consisting of approximately 90 amino acid residues, and an L chain as a protease domain. FXI alone does not have a property of adhering to a surface of a foreign substance. After FXI binds to a surface of a foreign substance via a high molecular weight kininogen (HMW-K), it is subject to limited hydrolysis by activated Factor XII (hereinafter also referred to as “FXIIa”), and the like, to be activated to FXIa. For the function of FXIa, the activation of Factor IX (hereinafter also referred to as “FIX”) in the presence of Ca2+ and the activity to degrade FXII, HMW-K and plasminogen under specific in vitro conditions have hitherto been reported, but an antitussive efficacy has not.    Patent Reference 1: JP-A-2000-344682    Patent Reference 2: JP-A-2003-327529    Patent Reference 3: JP-A-2007-099728    Non-patent Reference 1: Physiology and Plasticity of Putative Cough Fibres in the Guinea Pig: Pulm. Pharmacol Ther.: Undem B J, et al., 2002: 15: p 193-198